Many studies have demonstrated a role for a tissue-specific circadian clock in peripheral tissues such as liver, lung, tendon, and cartilage (Pekovic-Vaughan et al., 2014; Yeung et al., 2014; Gossan et al., 2013; Lamia et al., 2008). Studying the ways each peripheral clock is controlled and how it helps maintain normal physiology is crucial for of our understanding of basic biology, and for developing new therapeutic strategies. In this thesis, I have examined the role and regulation of the circadian clock in the mammary gland. Using an arrhythmic model to study the role of the clock in normal breast physiology, I observed a decrease in the number and proliferative capacity of stem cells in the epithelial ducts. This corresponds to a decrease in the sexual development of the breast during pregnancy and lactation, with reduced differentiation of epithelia into milk-producing alveoli. As the mouse ages, mammary tissue rhythms dampen, and this coincides with a similar reduction in the number of stem cells seen in the arrhythmic model. Dampening of tissue rhythms with age is not a cell intrinsic effect, and appears to be due to a change in the matrix. Aged mammary matrix contains more fibrillar collagen and is stiffer than its young counterpart. Reducing the stiffness of the cytoskeleton rescued the dampened rhythm in aged tissues, indicating a potential role for mechanical signalling in controlling the clock. Increased extracellular stiffness and intracellular tension dampens the epithelial circadian clock. This effect is mediated via actomyosin contractility and RhoA signalling, but other mechanotransduction pathways may also be important. Mechano-control of the clock is not limited to mammary epithelia, but is also seen in lung and skin epithelia. The phenotype is reversed in fibroblasts from these tissues, whereby the circadian rhythm is stronger in stiffer conditions. Finally, I find the human mammary clock is also mechanosensitive, which could contribute to stiffness-mediated cancer formation. Primary tumour cells have severely dampened rhythms compared to their normal counterparts, which could be a key mediator of proliferative and metastatic behaviour in these cells. Collectively these data reveal a novel mechanism of clock control which was seen in all cell types tested, and could be potentially important for the design and outcome of future circadian studies in breast biology and the wider field.
|Date of Award
|1 Aug 2018
- The University of Manchester
|Charles Streuli (Supervisor) & Qing-Jun Meng (Supervisor)